Anthrax is caused by the Gram-positive bacterium Bacillus anthracis. Disease in humans results from contact with infected animals, contaminated animal products or after exposure to accidentally or intentionally released spores of B. anthracis. The distribution of anthrax spores through the US mail has underscored the sense of urgency for the development of improved vaccines against this bacterial pathogen. The current human U.S. anthrax vaccine consists of aluminum hydroxide-adsorbed culture supernatant from a non-encapsulated strain of B. anthracis. This vaccine requires up to six intramuscular vaccine doses given over 18 months. In addition to Protective Antigen, the vaccine also contains a number of other bacterial and media-derived proteins which are likely responsible for the adverse effects experienced by some individuals and may reduce the efficacy of this vaccine. An ideal vaccine against anthrax should be safe, easy to deliver, provide long-lasting protection, require only one or a few doses, and be effective against different strains of B. anthracis. Recent advances in vaccine development have demonstrated that mucosal and transcutaneous immunization in the context of an appropriate adjuvant can produce both humoral and cellular antigen-specific immune responses in both the mucosal and systemic compartments of the host. Such needle-free immunizations are easy to deliver, cost-effective, and suitable for mass immunization campaigns, such as would be necessary during a national emergency or for vaccines delivered to underdeveloped countries. In this application, we will test the hypothesis that mucosal or transcutaneous vaccination with anthrax antigens can induce strong, sustained, and effective immune responses associated with protection against infection or can prime effectively for the induction of these responses. Challenge studies will allow us to correlate immune responses with protective efficacy and determine the contribution of mucosal immune responses to protection against pulmonary anthrax The results obtained from these studies will contribute to our understanding of the host responses involved in protection against anthrax and to the formulation of improved anthrax vaccines. This information may also be valuable in the development of similar prevention strategies against other potential agents of biowarfare/bioterrorism.